Chemistry Department, University of Toronto, Toronto, Ontario, Canada, M5S 2H8
Metal-catalysed decomposition of diazocarbonyl compounds is a well-established route to many heterocyclic structures [1]. The electron-deficient carbene or carbenoid formed in this reaction can intramolecularly attack a heteroatom's unshared pair of electrons giving an
intermediate ylide. The latter can then undergo a 1,2-shift to give products of formal heteroatom - H (or -R) carbenic insertion [1a-c] or can act as a dipole in cycloaddition reactions [1d,e].

The acid-catalysed decomposition of a-diazocarbonyl compounds is a
suitable way to generate other types of electron-deficient species, diazonium
ions and carbocations [2]. These transient species are usually intercepted by
external nucleophiles to give open-chain products, though the latter in some
cases can undergo cyclization to heterocyclic compounds [3]. In a few cases,
when a heteroatom is present in the diazo compound itself, nucleophilic
cyclization can occur [4]. In our opinion this promising route to heterocyclic
compounds appears to have escaped the attention of synthetic chemists, probably
because of insufficient information on the mechanism of these processes. In
this work we investigate acid-catalysed hydrolysis of two sample diazo ketones:
2,4,6-trimethoxydiazoacetophenone (1) which undergoes efficient
cyclization to 4,6-dimethoxy-3(2H)-benzofuranone (2), and
diazoacetophenone (3), which gives the intermolecular product,
2-hydroxyacetophenone (4).

Results

Product study

We found that 2,4,6-trimethoxydiazoacetophenone
(1) undergoes rapid hydrolysis in aqueous solutions in the presence of
perchloric acid to give 4,6-dimethoxy-3(2H)-benzofuranone (2).
Surprisingly enough, despite a huge excess of external nucleophile, 55.5 M of
H2O, and various acid concentrations in the range of 0.01 to 2 M, no open-chain
hydrolysis product was found, and 2 was always formed in quantitative
yield (Scheme 1).

Kinetics

The rates of hydrolysis of the diazo ketones 1 and 3
were determined spectrophotometrically by monitoring the change in UV
absorbance at lambda = 286, and 298 nm respectively.
Characteristic traces are shown in Figure 1

Figure 1 Hydrolysis of 1 in 0.0001 M HClO4 and of 3 in 0.04 M HClO4

We measured the rates of hydrolysis of both diazocompounds 1 and 3
in dilute aqueous perchloric acid solutions over the concentration range
pCH+= 1-4. The decay of diazoketones comformed to the first-order law well, and
the observed rates are summarized in Table S1
(for 1) and Table S2 (for 3). The data are displayed
as open circles (1) or open triangles (3) in the rate profiles of
Figure 2

Figure 2

The hydrolysis of both diazocompounds 1 and 3 is an
acid-catalysed process, and observed rates of hydrolysis show linear dependence
on perchloric acid concentration. Second-order rates calculated from these
slopes are shown in Table 1.

Table 1Summary of rate constants for the reactions of diazoketones 1 and 3a

One can see from Table 1 that trimethoxydiazoacetophenone 1 is over 600
times more reactive than parent 3. Rates of hydrolysis of diazoketones
1 and 3 were also measured in D2O solutions over the same acid
concentration range as the H2O data. Observed rates are summarized in Tables S3
and S4 respectively and displayed as filled
circles (1) or filled triangles (3) in Figure 2. Rate constants for
hydrolysis of 1 and 3 in D2O and solvent isotope effects on
these rates are listed in Table 1.

Diazoketones 1 and 3 show a dramatic difference in solvent
isotope effect on their rates of hydrolysis (Figure 2). In D2O, decomposition of
1 is substantially slower than in H2O, giving a solvent isotope effect
in the normal direction, kH+/kD+ = 2.37. This value and direction of
isotope effect is characteristic of rate-determining protonation on carbon [5].
On the other hand, the hydrolysis of diazoacetophenone 3 in D2O is
more than four times faster than in H2O; the solvent isotope effect is well
below unity, kH+/kD+ = 0.24. Such an inverse solvent isotope effect is a
clear sign of pre-equilibrium protonation.

We also found that hydrolysis of diazoacetophenone (3) in D2O is
accompanied by deuterium incorporation into it (Scheme 3).

Scheme 3

The low solubility of 3 in water prevents direct observation of
D-incorporation by NMR in a purely aqueous solution. This experiment was
therefor done in a 1:1 D2O - (CD3)2SO mixture at [DClO4] = 0.0005 M,
where isotope exchange was found to be more than ten times faster than
hydrolysis of 3: k(exchange) = (3.5 +/- 0.6) x 10-5 s
-1and k(hydrolysis)= (2.46 +/- 0.01) x 10-6 s-1 (Figure 3).

A mass spectroscopic analysis of a recovered sample of the diazo ketone
3, which was treated with a 0.001 M solution of DClO4 in D2O for 5
min (ca. 0.05 hydrolysis tau1/2), showed 90% D-enrichment. This is a clear
indication that in the case of the diazoacetophenone (3) pre-equilibrium
protonation occurs on carbon. From these data we can also estimate the rate of
hydronation of diazoketone 3 as kD+ca. 8 M-1
s-1. It is interesting to note that this value is very close to the
rate of protonation, measured directly, in the case of diazoketone 1.

The addition of iodide ion to the reaction mixtures (ionic strength is still
kept at 0.1 M) shows no effect on the rate of decomposition of
trimethoxydiazoacetophenone 1; however, it speeds up hydrolysis of 3
(Figure 4).

Discussion

The differences in kinetics of acid-catalysed hydrolysis of
diazoacetophenones 1 and 3 discussed above indicate that these
two process occur via different mechanisms. There are three generally accepted
mechanisms for acid-catalysed hydrolysis of a-diazoketones, all leading
to the same ultimate product

1 Rapid and reversible protonation on oxygen followed by nucleophilic
replacement of N2, (Scheme 4).

Scheme 4

2 Rapid and reversible protonation on carbon followed by nucleophilic
replacement of N2, (Scheme 5).

How could we distinguish between these three mechanisms? Mechanisms 1 and 2
involve pre-equilibrium protonation, and should give inverse solvent isotope
effects. On the other hand, rate-determining protonation in case 3 is usually
distinguished by isotope effects in the normal direction. Strong retardation of
acid-catalysed hydrolysis of 2,4,6-trimethoxydiazoacetophenone (1) in
D2O, kH+/kD+ = 2.37, indicates that this process occurs via
rate-determining protonation on the carbon of the diazo group.

The inverse solvent isotope effect, kH+/kD+ = 0.24, found in the
hydrolysis of diazoacetophenone (3), could be accomodated by both
mechanisms, 1 and 2. However, hydrolysis of diazoketones by reversible
protonation on carbon (mechanism 2) in D2O should be accompanied by hydrogen
exchange, while mechanism 1 gives no possibility of such exchange. The
D-incorporation into diazoketone 3, accompanying hydrolysis in D2O,
supports mechanism 2, indicating that reversible protonation of 3 also
occurs on carbon of the diazo group.

The rate-determining loss of nitrogen from protonated diazo ketone 3
can be monomolecular, A1 mechanism, or bimolecular, A2 mechanism, as shown in
Scheme 7.

Scheme 7

The nucleophilic assistance of diazoacetophenone (3) hydrolysis,
found in the experiments in the presence of iodide-ion, can be taken as
evidence of bimolecular A2 mechanism. This then allows us to complete the
scheme of diazoacetophenone (3) hydrolysis.Itstarts
with pre-equilibrium protonation to yield diazonium ion 3a. This ion
then undergoes rate-determining attack by nucleolphile (H2O or I- in
our case) to lose nitrogen and to give the final product, 2-hydroxyketone 4
(Scheme 8).

Scheme 8

The kinetic data for acid-catalysed cyclization of
trimethoxydiazoacetophenone 1 to benzofuranone 2 unfortunately
provides no information on steps beyond the rate-determining protonation.
However, it is reasonable to expect diazonium ion 1a (Scheme 9), formed
in this step, to have a reactivity towards external nucleophiles comparable to
that of 3a (Scheme 8), because the diazonium group in
ArCOCH2N2+-type ions is not conjugated with the aromatic ring. The
fact, that even in the wholly aqueous solutions we found no traces of trapping
of diazonium ion 1a by external nucleophile (H2O), indicates that this
ion is consumed in some other, much faster process. Most probably, protonation
of 1 gives diazonium ion 1a, which then undergoes rapid
nucleophilic attack by the oxygen of its ortho-methoxy group to give oxonium
ion 2a. Loss of methyl group from 2a in the form of primary
carbonium ion CH3+ seems to be very unlikely, and oxonium ion
2a, probably, undergoes hydrolysis by direct displacement to give
the final product, 4,6-dimethoxy-3(2H)-benzofuranone 2 (Scheme
9).

Scheme 9

This difference in rates and mechanisms between the hydrolysis of
1 and 3 shows that a heteroatom, occupying the right position in
a molecule of diazo compound, could be a very effective nucleophile in attacking
a protonated diazo group, thus providing a promising approach to heterocyclic
synthesis.

5,7-dimethoxy-3(2H)-benzofuranone (2). 40 mg of diazoketone 1
in 8 mL of THF was added dropwise to 30 mL of a stirred solution of
aqueous 2 M HCl at room temp. over a period of 5 min. The THF was then
removed in vacuum, and the aqueous phase was extracted three times with 20 mL
portions of chloroform. The combined organic phases were washed with water,
dried over MgSO4, and the solvent was removed to provide 32.5 mg (>98%) of
colourless crystals of 2. Mp (without purification!)
139-140oC (lit. 138-140oC [7]). The 1H,
13C, IR and mass spectra of the product are in a good agreement with
literature data [7,8].

Diazoacetophenone 3was prepared by literature procedure [9]. All
other materials were best available commercial grades.

Kinetics Rates of hydrolysis of diazoketones 1 and 3 were
determined spectrophotometrically by monitoring the changes in absorbance at
lambda = 282 and 298 nm respectively. The ionic strength of all
solutions was kept at 0.1 M by addition of sodium perchlorate, and the
temperature of the reaction mixtures was controlled at 25.0 +/-
0.05oC. Isotope exchange in D2O - (CD3)2SO solutions of
3 was monitored by NMR. Rate constants were calculated by least squares
fitting of an exponential function.